Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CRISPR]

Precise dynamic control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent gene promoters is essential for normal development and frequently corrupted in cancer. Using whole genome CRISPR/Cas9 screens we identify specific roles for MTF2-PRC2.1 and PCGF1-PRC1.1 polycomb complexes, and MLL1/2-COMPASS-like complex components in maintaining bivalency. Contrary to expectations, loss of Menin or inhibition of the Menin-MLL1/2 interaction, induces activation of bivalent genes via loss of polycomb-mediated repression and defines distinct roles for MLL1/2 and Menin in gene regulation. Whilst Menin and MLL1/2 contribute to maintenance H3K4me3 at active genes, a separate Menin-independent function of MLL1/2 opposes polycomb mediated repression at bivalent genes. MLL1/2 are essential for basal transcription and, although dispensable for transcription factor driven activation, facilitate transcriptional consistency during dynamic changes in gene expression. This functional partitioning of COMPASS complex components reveals therapeutic opportunities to target oncogenic and immunosuppressive functions of PRC2 through pharmacological inhibition of Menin. CRISPR screen for MHC low or high cells

在二价基因启动子（bivalent gene promoters）处，对激活性组蛋白H3赖氨酸4三甲基化（H3K4me3）与抑制性组蛋白H3赖氨酸27三甲基化（H3K27me3）实施精准动态调控，是维持正常发育的关键环节，且该调控过程在癌症中常发生紊乱。本研究通过全基因组CRISPR/Cas9筛选，鉴定出MTF2-PRC2.1、PCGF1-PRC1.1多梳蛋白复合物（polycomb complexes），以及MLL1/2-类COMPASS复合物组分在维持基因二价性中的特异性功能。与学界预期相悖的是，敲除脑膜瘤蛋白（Menin）或抑制Menin与MLL1/2的相互作用，可通过削弱多梳蛋白介导的基因抑制效应，激活二价基因，并明确了MLL1/2与Menin在基因调控中的差异化功能。尽管Menin与MLL1/2有助于在活性基因位点维持H3K4me3水平，但MLL1/2还存在一项不依赖Menin的独立功能，可在二价基因位点对抗多梳蛋白介导的基因抑制。MLL1/2对于基础转录过程至关重要；尽管其并非转录因子驱动的基因激活所必需，但可在基因表达的动态变化过程中维持转录的一致性。这种COMPASS复合物组分的功能分区特性，揭示了通过药理学抑制Menin，靶向PRC2的致癌与免疫抑制功能的治疗潜力。本数据集包含针对主要组织相容性复合体（Major Histocompatibility Complex, MHC）低表达或高表达细胞的CRISPR筛选数据。